DESCRIPTION: (Applicant's Abstract) Human prefrontal cortex (PFCx) is crucial for control of complex behavior involving sustained performance over delay periods. The current proposal focusses on delineating the physiological and behavioral mechanisms supporting this capacity. We accomplished the goals of the prior funding period by combining electrophysiological, behavioral and anatomical techniques in three sensory modalities to identify the contribution of PFCx, posterior association cortex and medial temporal region to the P300 event-related potential generated when attention is drawn to infrequent environmental events. This research revealed that the P300 is not a unitary event but instead measures attention-related neuronal activity in distributed cortical and limbic structures. Longer latency parietal maximal P300 activity (P3b) generated during voluntary attention was dependent on neuronal circuits in posterior association cortex. Shorter latency, fronto-central P300 activity (P3a) generated during involuntary attention to unexpected novel stimuli activated a distributed neuronal network involving dorsolateral prefrontal cortex and mesial temporal region in addition to posterior association cortex. These results indicate that a PFCx-hippocampal circuit is preferentially involved in processing of novel environmental events and suggest that this network may be the central nervous system manifestation of the orienting response. Activation of this circuit may underlie the classic Von Restorff memory effect wherein novel stimuli are better remembered. We also performed experiments providing physiological evidence of critic al PFCx involvement in sensory gating, sustained attention and motor control. Dorsolateral PFCx damage disinhibited evoked responses generated in primary auditory and somatosensory cortex and preliminary behavioral experiments indicate that distractibility die to inability to inhibit extraneous sensory inputs contributes to the prefrontal deficit observed in delay tasks. Sustained attention during delay intervals as measured by the Contingent Negative Variation was also found to be dependent on PFCx. The results of these experiments conducted in the prior funding period form the foundation for the current proposal. We will perform inter- and intra-modality experiments employing electrophysiological, behavioral and neuroanatomical methods in the auditory, somatosensory and visual modalities to: 1) investigate whether sensory gating deficits contribute to PFCx deficits in delay tasks, 2) further elucidate the role of PFCx in sustained attention and 3) determine if a PFCx- hippocampal circuit underlies memory for novel events. The proposed work will contribute to our understanding of the role of PFCx in both normal cognition and in major neurological and psychiatric disorders with PFCx dysfunction.